Chemoattractant cytokines, Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that are released by a wide variety of cells to promote recruitment and activation of cells such as T and B lymphocytes, eosinophils, basophils, and neutrophils (Luster et al. New Eng. J. Med, 1998, 338, 436). The chemokines are related in primary structure and contain four conserved cysteines, which form disulfide bonds. The chemokine family includes the C—X—C chemokines (α-chemokines), and the C—C chemokines (β-chemokines), in which the first two conserved cysteines are separated by an intervening residue, or are adjacent, respectively (Baggiolini, M. and Dahinden, C. A., Immunology Today, 1994, 15, 127).
Chemokines exert their biological activity by binding to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (Horuk, Trends Pharm. Sci. 1994, 15, 159) which are termed “chemokine receptors”. On binding their cognate ligands, chemokine receptors then transduce signals important for the development and trafficking of specific leukocyte subsets (Baggiolini, et. al., Nature 1994, 15, 365). The chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, and allergic diseases, disorders, and conditions, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (see, Carter, Current Opinion in Chemical Biology 2002, 6, 510; Trivedi et al., Ann. Reports Med. Chem. 2000, 35, 191; Saunders et al., Drug Disc. Today 1999, 4, 80; and Premack et al., Nature Medicine, 1996, 2, 1174). Accordingly, agents that block the interaction of chemokines with their cognate receptors would be useful in treating inflammatory, allergic, and autoimmune diseases, disorders, or conditions caused by aberrant activation of leukocytes or lymphocytes.
CCR2 is a chemokine receptor expressed on monocytes which recognizes the ligands MCP-1, MCP-2, MCP-3, and MCP-4 (see, Berkhout, et al., J. Biol. Chem. 1997, 272, 16404. It has been implicated that the interaction of monocyte chemoattractant protein-1 (MCP-1) and its receptor (CCR2) plays a role in the pathogenesis of inflammatory, allergic, and autoimmune diseases (for example rheumatoid arthritis, multiple sclerosis, COPD, neuropathic pain, asthma, and atherosclerosis) by attracting leukocytes to sites of inflammation and subsequently activating these cells. When the chemokine MCP-1 binds to CCR2, it induces a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of leukocyte migration. (see Dawson, et al., Expert Opin. Ther. Targets, 2003, 7, 35; Gongh et al., J. Exp. Med. 1997, 181, 131; Izikson, et al., Clin. Immunol. 2002, 103, 125; Donnelly et al., Drugs, 2003, 63, 1973; Leonard, E. J. Challenges Mod. Med., 1994, 3, 25; and Ross, R. New Engl. J. Med. 1999, 147, 213). In particular, monocyte chemoattractant protein-1 (MCP-1) is believed to be primarily responsible for the selective recruitment of leukocytes to the site of inflammation by binding to its receptor CCR2 on the surface of monocytes and macrophages (Rollins et al., Blood, 1997, 90, 909; Howard et al., Trends Biotechnol. 1996, 14, 46; Saunders et al., Drug Discovery Today, 1999, 4, 80; Murphy et al., Pharmacologic Rev., 2000, 52, 145; and Horuk, R. Cytokine Growth Factor Rev., 2001, 12, 313). The importance of the MCP-1/CCR2 interaction has been demonstrated by experiments with genetically modified mice (see, Bao, et al., J. Exp. Med. 1998, 187, 601; Boring et al., J. Clin. Invest. 1997, 100, 2552; Kuziel et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 12053; and Kurihara et al., J. Exp. Med. 1997, 186, 1757). Several studies have also been published indicating that therapeutic intervention at the CCR2 receptor via inhibition of the interaction between MCP-1 and CCR2 may have beneficial effects in a variety of inflammatory, allergic, and autoimmune diseases. For example, studies completed to date have indicated that the antagonism of the MCP-1/CCR2 interaction may be useful in treating rheumatoid arthritis; ameliorate chronic polyadjuvant-induced arthritis (Youssef et al., J. Clin. Invest. 2000, 106, 361); collagen-induced arthritis (Ogata et al., J. Pathol. 1997, 182, 106); streptococcal cell wall-induced arthritis (Schimmer et al., J. Immunol. 1998, 160, 1466); MRL-lpr mouse model of arthritis (Gong et al., J. Exp. Med. 1997, 186, 131); atherosclerosis (Rezaie-Majd et al, Arterioscler. Thromb. Vasc. Biol. 2002, 22, 1194-1199; Gu et al., Mol. Cell. 1998, 2, 275; Gosling et al., J. Clin. Invest. 1999, 103, 773; Boring et al, Nature 1998, 394, 894; and Ni et al. Circulation 2001, 103, 2096-2101); multiple sclerosis (Iarlori et al., J. Neuroimmunol. 2002, 123, 170-179; Kennedy et al., J. Neuroimmunol. 1998, 92, 98; Fife et al., J. Exp. Med. 2000, 192, 899; and Izikson et al., J. Exp. Med. 2000, 192, 1075); organ transplant rejection (Reynaud-Gaubert et al., J. of Heart and Lung Transplant., 2002, 21, 721-730; Belperio et al., J. Clin. Invest. 2001, 108, 547-556; and Belperio et al., J. Clint Invest. 2001, 108, 547-556); asthma (Gonzalo et al., J. Exp. Med. 1998, 188, 157; Lukacs, et al., J. Immunol. 1997, 158, 4398; and Lu et al., J. Exp. Med. 1998, 187, 601); kidney disease (Lloyd et al., J. Exp. Med. 1997, 185, 1371; and Tesch et al., J. Clin. Invest. 1999, 103, 73); lupus erythematosus (Tesch et al., J. Exp. Med. 1999, 190, 1813); colitis (Andres et al., J. Immunol. 2000, 164, 6303); alveolitis (Jones, et al., J. Immunol. 1992, 149, 2147); cancer (Conti, et al., Seminars in Cancer Biology 2004, 14, 149; Salcedo et al., Blood 2000, 96, 3440); restinosis (Roque et al. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 554-559); inflammatory bowel disease (Reinecker et al., Gastroenterology 1995, 108, 40; and Grimm et al., J. Leukoc. Biol. 1996, 59, 804); brain trauma (King et al., J. Neuroimmunol. 1994, 56, 127; and Berman et al., J. Immunol. 1996, 156, 3017); transplant arteriosclerosis (Russell et al., Proc. Natl. Acad. Sci. USA 1993, 90, 6086); idiopathic pulmonary fibrosis (Antoniades et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371); psoriasis (Deleuran et al., J. Dermatol. Sci. 1996, 13, 228; and Gillitzer et al., J. Invest. Dermatol. 1993, 101, 127); HIV and HIV-1-associated dementia (Garzino-Demo, WO 99/46991; Doranz et al., Cell 1996, 85, 1149; Connor et al., J. Exp. Med. 1997, 185, 621; and Smith et al., Science 1997, 277, 959); and neuropathic pain (Abbadie, et al., Proc. Natl. Acad. Sci. USA 2003, 100, 7947). Similarly, demonstration of the importance of the MCP-1/CCR-2 interaction has been reported in the literature. For example, Lu et al., J. Exp. Med. 1998, 187, 601; Boring et al., J. Clin. Invest. 1997, 100, 2552; Kuziel et al., Proc. Natl. Acad. Sci. USA 1997, 94, 12053; and Kurihara et al., J. Exp. Med. 1997, 186, 1757.
Accordingly, agents that inhibit the interaction of MCP-1 and CCR2 would be useful in the treatment of a variety of inflammatory, allergic and autoimmune diseases, disorders, or conditions.